Method of inducing anesthesia with 2-bromo-1 1 2 3 3-pentafluoropropane

ABSTRACT

2-BROMO-1,1,2,3,3-PENTAFLUOROPROPANE IS EMPLOYED AS AN ANESTHETIC AGENT BY ADMINISTRATION BY INHALATION.

United States Patent U.S. Cl. 424-350 1 Claim ABSTRACT on THE DISCLOSURE2-bromo-1,l,2,3,3-pentafluoropropane is employed as an anesthetic agentby administration by inhalation.

CROSS REFERENCES TO RELATED APPLICATIONS This is a continuation ofco-pending application Ser. No. 858,206, filed Mar. 10, 1969, nowabandoned, which in turn is a division of application Ser. No. 664,604,filed Aug. 31, 1967, now U.S. Pat. 3,480,683. Application Ser. No.664,604 is a continuation-in-part of application Ser. No. 538,523, filedFeb. 2, 1966, now U.S. Pat. 3,362,874.

This invention relates to a novel bromopentafluoropropane. Moreparticularly, this invention relates to a monobromopentafluoropropanehaving a bromine atom substituted on the number two carbon atom, namely,2- bromo 1,1,2,3,3 pentafluoropropane.

It is known that certain halogenated alkanes are useful inhalationanesthetics. Chloroform and halothane are well-known examples of suchcompounds which are derivatives of the lower alkanes, methane andethane, respectively. More recently, it has also been disclosed .thatcertain halogenated fluoropropanes are useful inhalation anesthetics.Thus, Dishart, U.S. Pat. 3,034,959, discloses the inhalation anestheticuse of 3 bromo-1,1, 2,2 tetrafluoropropane and Belgian Pats. 663,478 and668,605 disclose the inhalation anesthetic use of 3-bromo-3-chloro-1,1,2,2-pentafluoropropane.

Position isomers of the monobromopentafluoroproipane of the presentinvention also are known. Thus, 3-bromo- 1,1,1,2,2 pentafluoropropane isdisclosed by McBee et al., 77 J. Am. Chem. Soc. 3149 (1955);3-bromo-l,l,l, 3,3-pentafiuoropropane is disclosed by Muray, BritishPat. 908,110; 2 bromo l,1,1,2,3 pentafluoropropan'e is disclosed byRausch et al., 28 J. Org. Chem. 494 (1963); and 1- and 3-bromo 1,1,2,2,3pentafluoropropanes are disclosed in a dissertation by Beck,Reactivities of Aliphatic Fluorides, The Ohio State University (1959).

Two of the above position isomers of the monobromopentafluoropropane ofthe present invention have been further disclosed as having inhalationanesthetic properties. Thus, Raventos, British Pat. 913,143, disclosesthe inhalation anesthetic properties of 3 bromo 1,l,1,3,3-pentafluoropropane and Burns et al., 17 Anaesthesia 337-343 (1962),disclose the inhalation anesthetic properties of3-br0mo-1,l,1,2,2-pentafiuoropropane.

It has now been found that the novel monobromopentafluoropropane asdefined herein is a useful inhalation anesthetic which has an inhalationmargin of safety in mice which is not only substantially higher than themargin of safety of the abovementioned position iso- ICC mers disclosedby Raventos and Burns et al., but is also substantially higher than themargin of safety of the inhalation anesthetics in current use, namely,ether, chloroform, and halothane. As such, the novel compound of thisinvention holds good promise as an effective and useful agent forinducing anesthesia in man.

The novel monobromopentafiuoropropane of this in-. vention also isstable to soda lime as distinguished from the position isomer ofRaventos, 3-bromo 1,1,1,3,3- pentafluoropropane, which is not stable tosoda lime. This property of the novel compound of the present inventionmakes it useful in conventional re-circulation apparatus which employssoda lime for the absorption of carbon dioxide from the patientundergoing anesthesia.

The novel inhalation anesthetic compound of the pres ent invention alsohas been found to be nonflammable in air and noneX'plosi-ve in oxygen atambient temperatures. Its lower flammability limit in oxygen of about 9%by volume is well above the useful concentrations for inhalationanesthesia in man which is not more than about 5% by volume. Moreover,the flammability margin of safety of the novel compound of thisinvention is sub.- stantially greater than the margin of safety of theposition isomer of Burns et al., 3-bromo 1,1,1,2,2 pentafluoropropane.

The novel 2 bromo 1,1,2,3,3 pentafluoropropane of the present inventionis a clear liquid at normal room temperature and has a boiling point of60.2- C. at 736 mm. Hg. It can be conveniently stored in containersnormally used for conventional anesthetics of comparable boiling point,e.g., halothane. It can be administered by apparatus or machinesdesigned for the vaporization of liquid anesthetics and admixturesthereof with oxygen, air or other gaseous mixtures containing oxygen inamounts capable of supporting respiration.

For use in anesthesia, the 2 bromo 1,1,2,3,3 pentafluoropropane shouldbe free of toxic impurities which may be present according to theparticular process used for its manufacture. This compound can, however,be used in admixture with pharmaceutically acceptable diluents andstabilizers, e.g., thymol, or one or more of the known inhalationanesthetics, e.g., nitrous oxide, ether, halothane, chloroform,cyclopropane, methoxyfiuorane, and the like.

The novel monobromopentafluoropropane defined here- .in can beconveniently prepared by elimination of a .Mar. 10, 1969, now U.S. Pat.3,458,584.

A preferred method .of preparation of the novel.monobromopentafluoropropane of this invention comprises the employmentof a mixture of a metal oxide, for example, lead dioxide, and sulfurtetrafluoride for the selective addition of fluorine to the double bondof the 2 bromo 1,3,3 trifluoropropene in an autoclave at a temperatureof about C. for about five hours.

Although the above methods of preparation and reaction conditions arespecifically described, it will be understood that the novelmonobromopentafiuoropropane of this invention is not limited to thisspecific method of preparation. For example, other methods of fluorine.addition to the double bond in 2 bromo 1,3,3 trifluoropropene may beemployed to prepare the novel anesthetic agent 2 bromo 1,1,2,3,3pentafiuoropropane. Thus, elemental fluorine, high valency metallicfluorides (such as, for example, cobalt trifluoride, silver difiuoride,antimony pentafluoride, manganese trifluoride and cerium tetrafiuoride),xenon tetrafluoride or a mixture of lead dioxide and anhydrous hydrogenfluoride and the like can be used to fluorinate the intermediate2-bromo-l,3,3- trifluoropropenes.

The following examples will further illustrate the present invention,although the invention is not limited to these specific examples. Allpercentages and parts herein are on a weight basis unless otherwisespecified.

EXAMPLE 1 1,1,3,3-tetrafluoropropan-2-ol (1) Hydrogen at the rate ofone-half liter per minute was bubbled through1,3-dichloro-l,l,3,3-tetrafluoroacetone at "4 C. The mixture of vaporspassed through a Pyrex tube (45 cm. x 1.9 cm. LD.) containing 2%palladium on carbon granules (4-12 mesh) and heated to 200 C. Thereaction products were condensed in a trap cooled by Dry Ice. A 750:1ratio by weight of dichlorotetrafluoroacetone to palladium is optimum.

In a typical run 1250 grams (6.28 moles) of dichlorotetrafiuoroacetonewas vaporized with hydrogen during 22 hoursand the mixture passed over85 grams of palladium-carbon catalyst. Fractional distillation of thereaction products gave 704 grams (5.33 moles, 85% of theory) of crudealcohol (I) B.P. 106-109" C., suitable for use in the next step.

Alternatively, the alcohol 1) can be prepared by reduction of1,1,3,3-tetraliuoroacetone with sodium borohydride. The alcohol (I)obtained in this manner had B.P. l0709 C., 12 1.333. The identity of thealcohols prepared in these two ways was confirmed by infrared spectra.

EXAMPLE 2 1,1,3,3-tetrafluoro-2-propyl-p-toluenesulfonate (II) A mixtureof crude 1,1,3,3-tetrafluoropropan-2-ol (I) (315 g., 2.4 moles),p-toluenesulfonyl chloride (460 g., 2.4 moles) and 600 ml. of water wasstirred as N sodium hydroxide (514 ml., 2.57 moles) was added during 1.5hours, and the temperature was maintained between 25 C.-40" C. Stirringwas continued for 16 hours. The lower layer of crude ester (II) wasseparated, stirred, evachated to between 25-40 mm. Hg and heated to 125C.

until volatile impurities ceased to be removed. Five hundredeighty-three grams (2.04 moles, 85% of theory) of crude ester (II)suitable for use in subsequent steps was obtained. Crystallization fromligroin gave ester (11),

MP. 31" C., a 1.466. v

Analysis.-Calculated for C H F4O S (percent): C, 41.91; H, 3.52; S,11.20. Found (percent): C, 42.13; H, 3.63; S, 10.95.

EXAMPLE 3 2-bromo-1,1,3,3-tetrafiuoropropane (III) a mixture of III,1,4-dioxane and water, from which the III was purified by successivewashings with water and aqueous 60% sulfuric acid. It was neutralized bya wash with cold dilute aqueous sodium hydroxide. The crude bromide(III) amounted to 314 grams (81.5% of theory). Fractional distillationgave 256 grams of bromide (III),

.b .82.6-82.8 C. Pure (99.9% by G.L.C.) bromide log P=8.1590

Its 60 mo. nuclear magnetic resonance (NMR) and infrared spectraconfirmed the CI-lF -CH Br-CI-IF structure.

EXAMPLE 4 Cisand trans-Z bromo-1,3,3-trifluoropropenes (IV) A mixture of2-bromo-1,1,3,3-tetrafluoropropane (III) (368 g., 1.88 moles) andlow-moisture (about 2% water) soda lime (180 g.) was heated to boilingunder total reflux for about sixteen hours. Gas liquid chromatographic,infrared, and proton nuclear magnetic resonance analyses of the liquidreaction product showed essentially complete conversion to a mixture ofcisand trans-2-bromo-1,3,3- trifiuoropropenes (IV). The ratio of thecisand transpropene isomers produced was about 13:1. The predominantpropene has a longer retention time than either the other propene or thestarting propane on a column packed with 20% diisodecylphthalate onChromasorb P at C. to C. Fractional distillation of the propene mixturedid not aiford an efiicient separation, and the cisand trans-propeneisomers distilled concurrently, b 1 77.5-78.0 C. (290 g., 1.66 moles,88% yield). The last fraction collected afforded the purest product, b78.0 C., d 1.8429, 113 1.3961, and is 99.4% the predominant propene and0.54% the other propene.

EXAMPLE 5 Z-bromo-1,l,2,3,3-pentafluoropropane (V) A 300 ml. Hoke highpressure (5,000 p.s.i.) cylinder equipped with a 2,600 to 3,000 p.s.i.rupture disc assembly and a Hoke M327A needle valve was charged with48.6 grams of PbO After pressure checking the system at p.'s.i.', thecontents were thoroughly vacuum degassed while the cylinder was heatedexternally. Next, 23.6 grams of 2-bromo-1,3,3-trifluoropropene (IV) weredistilled in on a high vacuum system after which the vessel was allowedto warm to ambient temperature. This warming procedure is believed to bedesirable since the olefin can then act as a reaction medium and heatsink for the exothermic reaction of PbO' and SF, carried out in the nextstep. The vessel was then precooled to 196 C. and 38 ml. SF, (73 g., at78 C.) were distilled in, after which the vessel was allowed to warmvery slowly to ambient temperature by placing it in a cold Dewar flask.The next morning the cylinder was placed in a rocking furnace, warmed to100 C., and rocked for five hours. After cooling, the volatile contentswere removed under vacuum through traps at 78 C. and 196 C. placed inseries. The -78 C. trap usually contained 24 to 26 grams of productwhich analyzed from 75 to 95% 2-bromo-1,1,2,3,3-pentafluoropropane bygas chromatography. Extraction of this product with dilute aqueousalkaline sodium sulfite, drying of the washed product, and fractionaldistillation gave 2-bromo-1,1,2,3,3-penta'- fluoropropane; b 60.2" C.,(1 1.86, having a purity of 99.9% as determined by gas-liquidchromatography. The molecular structure CH'F CFBrCI-IF was confirmed byproton nuclear magnetic resonance and infrared spectra.

EXAMPLE 6 Inhalation of the vapor of 2-bromo-1,1,2,3,3-pentafluoropropane admixed with air in the manner described by Robbins, 86 J.Pharmacol. Exper. Therap. 197-204 (1946), produced anesthesia in whitemice. The minimum concentration by volume percent required to producefull anesthesia (loss of negative righting reflex) in 50% of the testanimals in five minutes, AC and the minimum concentration by volumepercent required to kill 50% of the test mice in five minutes, LC aregiven in Table I, be

low. The inhalation margin of safety asmeasured in mice by the ratio LC/AC is also given in Table I. For purposes of comparison, similar datawhich were obtained under the same conditions as for the above compoundare given for three inhalation anesthetics in current use, namely,ether, chloroform and halothane, and for the position isomers3-bromo-1,1,1,2,2-pentafiuoropropane and3-bromo-l,1,1,3,3-pentafiuoropropane disclosed by Burns et al., andRaventos, respectively, as having inhalation anesthetic properties. Thenumber of mice used with the different anesthetic agents varied from 25to 92 for determining each of the AC and LC doses.

TABLE I.-INH ALATION ANESTHESIA IN MICE Compound A050 L050 Lose/AC5 CHFCFIBrCHFg 0. 73 3. 67 5. 0 CF3CF2CH3BI 1.71 5. 58 3. 3 CF3CFz-CF2BI 1.62 5. 84 3. 6

ther 3. 69 12. 0 3. 2 chloroform O. 94 2. 56 2. 7 Halothane O. 78 2. 623. 4

Surgical anesthesia (stage 111, plane 2) was induced in two dogs withabout 3% by volume of 2-bromo-1,1,2,3,3- pentafluoropropane in oxygenand maintained for 30 to 60 minutes with about 1.5% to 2.5% by volume ofthis anesthetic agent in oxygen. For purposes of comparison, surgicalanesthesia was induced in four dogs with 2% to 4% by volume halothane inoxygen and maintained for 60 minutes with 1% to 2% by volume ofhalothane in oxygen.

The anesthetic agent was administered via an endotracheal catheter withinflation cuffs in a non-rebreathing system subsequent to initialanesthesia with sodium methohexital and pretreatment with atropinesulfate and heparm.

Heart rate and myocardial responses were determined from EKG records.Spontaneous respiratory rate and respiratory minute volume weremaintained by means of a pressure change transducer and a wet-testmeter, respectively. The arterial blood pressure was monitored, andblood samples were withdrawn for determinations of blood gases and pH.

Anesthesia with 2-bromo-l,1,2,3,3-pentafiuoropropane in two dogs wasequivalent to halothane anesthesia. Both compounds produced a fall indiastolic blood pressure below 70 mm. Hg, and a decrease in heart rate.However, normal spontaneous respiratory rate and minute volume andnormal pCO values were observed in anesthesias with both compounds. TheEKG records were also normal with the exception of T-wave inversionduring anesthesia with both compounds.

EXAMPLE 8 The soda lime stability of the novel inhalation anesthetic ofthe present invention was determined essentially according to theprocedure of Glover and Hodgson, 16 Anesthesia 19-23 (1961). The liquidanesthetic (0.65 ml.) and soda lime (0.50 g., 8-12 mesh, 15%20% byweight of water) were sealed in a glass ampule and heated at 70 C. forthree hours and then analyzed by gas-liquid partition chromatography.For purposes of comparison, a liquid anesthetic blank was treated in thesame way in the absence of soda lime. The chromatographic results aregiven in Table II, below, in which R.T. is retention time in minutesfrom air and Area percent is 100 times the ratio of the area under apeak to the total area under TABLE II.SODALIll/IE STABILITY OFANESTHETICS Blank Soda lime treated Area Area, Area, perperper- OompoundR.T. cent R.T. cent R.T cent CHFzOFB1CHFz 7. 5 99. 9 0. 43 0. 50 7. 599. 5 Halot'nane 7. 2 99. 9 4. 2 0. 20 7. 2 99. 8

The remarkable soda lime stability of the novelmonobromopentafluoropropane of this invention is shown by the highcorrespondence between the 99.9+ and 99.5 Area percents after 7.5minutes of retention time in the blank sample and the soda lime treatedsample, respectively.

EXAMPLE 9 The flammability of gaseous mixtures of the novel inhalationanesthetic of the present invention and air or oxygen was determined atroom temperature and atmospheric pressure by visualization of thedownward propagation of a flame in a glass bottle having a cylindricalportion 2.3 inches ID. x 3.5 inches in height. The bottle was flushedwith pure oxygen or air, a known quanity of liquid anesthetic was addedrapidly, and the bottle was closed with a ground glass stopper. Thebottle was then rotated and shaken until the liquid anesthetic wascompletely vaporized and uniformly mixed with oxygen or air. The stopperwas then removed and immediately a burning stick inserted in the bottle1.5 to 2.0 inches below the bottle mouth.

The concentration by volume percent of the gaseous anesthetic in oxygenor air was calculated by well-known computation means employing theknown volume of the stoppered bottle (i.e., the volume of the containedoxygen or air), the known volume of the added liquid anesthetic, theknown densities and molecular weights and application of the ideal gaslaw to compute the gaseous volume of the anesthetic sample.

The lower flammability limits in oxygen, LFIO and in air, LFlAir, asdetermined by the above procedure are given in Table III, below. Theseflammability limits are stated as a range of two concentrations byvolume percent; downward flame propagation was observed at the higherconcentration but not at the lower concentration of the anesthetic inthe gaseous mixture. The median anesthetic concentration for mice, AC asdetermined in Example 6, above, is also given in Table III. The ratio,LFlOg/ AC herein referred to as the flammability margin of safety, isalso given in Table III. For purposes of comparison, similar data whichwere obtained under the same conditions as for the above compound aregiven for the position isomer 3-bromo-1,1,l,2,2-pentafluoropropane,which has been previously disclosed as having inhalation anestheticproperties.

TABLE III.FLAMMABILITY OF ANESTHETICS L 10 Compound LFlOz LFlAir AC5;5.0. 1 CHF2-OFBrCHFz 8.9-9.6 Nonflammable 0.71 1 CF2CFtCHzBr 11.0-11.6do 1.71 6.2

As will be readily apparent to those skilled .in the art, other examplesof the herein-defined invention can be devised after reading theforegoing specification and claim appended hereto by variousmodifications and adaptations without departing from the spirit andscope of the invention. All such modifications and adaptations areineluded within the scope of the invention as defined in the appendedclaim.

What is claimed is:

1. The method of inducing anesthesia in animals which comprisesadministering by inhalation to said animals an eifective amount of2-bromo-1,1,2,3,3-pentafluoropropane for inducing anesthesia.

References Cited UNITED STATES PATENTS Downing et a1. 260 653. McBee eta]. 260653 Sucking et a1. 2606-53 Muray et a1. 260-653 Regan 260'-653Regan 424350 Regan 42A--350 JEROME D. GOLDBERG, Primary Examiner

